Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects half of the adult population worldwide. The chronic inflammation triggered by H. pylori can lead to variable outcomes, such as peptic ulcers and gastric cancer, depending on the degree and extent of gastritis so caused. Although a predominant Th1-polarized mucosal immune response is activated in the host, the immune response is not sufficient to mount protective immunity against H. pylori, resulted in chronic infections and development of gastric pathologies in certain patient. Previous studies have revealed that H. pylori lysates can inhibit mitogen-induced T-cell proliferation, indicating that there are certain factors in the lysate relating to immunosuppressive activities. Such factors attenuate the T-cell activity, independent of the bacterial virulence genes CagA and VacA. Several mechanisms have been proposed to explain how H. pylori directly or indirectly suppresses T-cell-mediated immunity: H. pylori could inhibit T-cell proliferation and TCR expression by arginase, stimulate the release of the inhibitory cytokine TGF-β, interfere with invariant chain-dependent antigen presentation via VacA, negatively regulate the functions of DC via CagA phosphorylation, or suppress phagocytosis by professional phagocytes via VirB7 and VirB11.
Despite the possible involvement of the above-mentioned mechanisms, regulatory T-cells (Treg cells) are currently considered the main regulatory components in the inhibition of T-cell activity and in the balance of inflammation and bacterial persistence. In 2003, CD4+CD25+ T-cells were reported to be involved in H. pylori-induced immunopathology and colonization. Further investigations showed that host Treg cells are crucial in protecting an H. pylori-infected host against excessive gastric inflammation and disease syndromes, while at the same time promote bacterial colonization at the gastric and duodenal mucosa. Moreover, the expression of B7-H1 by gastric epithelial cells promotes the development of CD4+CD25+FoxP3+ Treg cells following H. pylori exposure, which indicates that this pathogen promotes the induction of host Treg cells. Subsequent studies examined the functions of these H. pylori-induced Treg cells and showed that they can suppress the activity or induce the anergy of H. pylori-specific effector T cells. In addition, H. pylori-induced gastritis is associated with a recruitment of naturally occurring FoxP3+ Treg cells that correlate with the degree of bacterial colonization and mucosal TGF-β1 expression. Collectively, these findings indicate that host Treg responses induced by H. pylori infection are important regulators of the immune response to H. pylori and are involved in the pathogenesis of H. pylori-related diseases.
H. pylori heat shock protein 60 (HpHSP60) can induce the expression of proinflammatory cytokines and TGF-β1 in monocytes. HpHSP60 has been reported to be expressed in the bacterial cell wall, associated with urease, and can function as an adhesive molecule for gastric epithelial cells. In addition, the administration of an anti-HSP60 antibody was found to interfere with the growth of H. pylori. Therefore, HpHSP60 is not only an essential factor for the viability of H. pylori but is also an important product that facilitates colonization of the human stomach. However, many studies have shown that HpHSP60 acts as a potent immunogen, leading to the strong induction of proinflammatory cytokines, such as TNF-α, IL-8, and IL-6. These cytokines determine inflammation at the site of infection, and such HpHSP60-induced inflammation might have the potential to promote processes of malignant tumorigenesis, including angiogenesis and metastasis. HpHSP60 is also an important virulence factor for H. pylori infection in a human host.
Taken together, the relationship between HpHSP60 and Treg cells is intriguing and deserves further investigations. However, most past researches focus on inflammation induced by HpHSP60. Very few researches talked about the relationship between HpHSP60 and the immunosuppressive reactions expressed in a host.
U.S. Pat. No. 6,403,099 disclosed conjugated compounds comprising a heat shock protein and capsular oligosaccharide or polysaccharide. The compounds are capable of inducing formation of anti-polysaccharide antibodies. The heat shock protein includes H. pylori heat shock protein.